VIP interneuron impairment promotes in vivo circuit dysfunction and autism-related behaviors in Dravet syndrome

Dravet syndrome (DS) is a severe neurodevelopmental disorder caused by loss-of-function variants in SCN1A, which encodes the voltage-gated sodium channel subunit Nav1.1. We recently showed that neocor-tical vasoactive intestinal peptide interneurons (VIP-INs) express Nav1.1 and are hypoexcitable in DS (Scn1a+/-) mice. Here, we investigate VIP-IN function at the circuit and behavioral level by performing in vivo 2-photon calcium imaging in awake wild-type (WT) and Scn1a+/- mice. VIP-IN and pyramidal neuron activa-tion during behavioral transition from quiet wakefulness to active running is diminished in Scn1a+/- mice, and optogenetic activation of VIP-INs restores pyramidal neuron activity to WT levels during locomotion. VIP-IN selective Scn1a deletion reproduces core autism-spectrum-disorder-related behaviors in addition to cellular-and circuit-level deficits in VIP-IN function, but without epilepsy, sudden death, or avoidance behav-iors seen in the global model. Hence, VIP-INs are impaired in vivo, which may underlie non-seizure cognitive and behavioral comorbidities in DS.

Automated summary

DS is a severe neurodevelopmental disorder caused by loss-of-function variants in SCN1A. In this study, the impaired function of VIP-INs in DS mice was observed, and optogenetic activation of VIP-INs restored neuronal activity. These findings suggest that the dysfunction of VIP-INs may underlie the cognitive and behavioral comorbidities in DS.